Discovery of a Novel DYRK1A Mutation (c.524del) in Intellectual Development Disorder Autosomal Dominant 7 (MRD7): A Comprehensive Case Analysis

Dual-specificity tyrosine kinase 1A (DYRK1A) is a member of the CMGC family that is linked to a multitude of neuronal development pathways. Both overexpression and insufficiency of this gene are associated with many recognizable disorders, including Down syndrome and DYRK1A-related intellectual disability syndrome which is characterized by distinct physical features with microcephaly and global developmental delay. We report a case of DYRK1A-related intellectual disability syndrome caused by a novel mutation.


Introduction
DYRK1A mutations have been linked to multiple neurological disorders including Down syndrome, intellectual development disorder autosomal dominant 7 (MRD7), dementia, Alzheimer's disease, fronto-temporal degeneration, Huntington's disease, and Parkinson's disease.Tis is due to the gene's extensive involvement in neuronal development and signaling pathways.DYRK1A is located in human chromosome 21q22.2,known as the Down syndrome critical region (DSCR).Activation of DYRKs depends on the autophosphorylation of a tyrosine residue in the activation loop [1].Mutations lead to DYRK1A proteins that lack all or part of the kinase domain and are catalytically inactive [2].Overexpression of DYRK1A is strongly associated with Down syndrome, whereas haploinsufciency is associated with MRD7.Mutations that result in haploinsufciency include microdeletions, translocations, single nucleotide variants, or insertions/deletions [3,4].
Te phenotypic presentation of these patients usually includes microcephaly, intellectual disability, speech delay, facial dysmorphisms, seizures, vision abnormalities, and feeding difculties.Te facial dysmorphisms stay consistent across afected individuals, with MRD7 patients having posteriorly rotated and protruding ears with thick and overfolded helices, prominent eyebrows, high anterior hairlines, and retrognathia.Patients can also have foot abnormalities with proximal placement of the frst toe, crooked toes, and syndactyly of the second and third toes [5].
Here, we present the case of a patient with a clearly pathogenic mutation in DYRK1A that has not been described in the literature.

Clinical Case Presentation
A 3.5-year-old male was referred for the frst time to a medical genetics clinic by his pediatrician for developmental delay associated with cortical nodular heterotopia on brain imaging.Maternal drug screening was positive for buprenorphine.He was born via spontaneous vaginal delivery at 40 weeks with APGARs of 7 and 9 at 1 and 5 minutes, respectively.At birth, his neonatal abstinence score was 17 and he was placed on morphine replacement therapy.He also had poor feeding while in the neonatal intensive care unit.Auditory brainstem response testing was normal at birth.Metabolic newborn screen was normal.
Circumcision was performed on day of life 5. Birth weight was 3425 g, and discharge weight was 3195 g.At 2 months of age, his height was below 1 percentile and normal motor development with borderline delayed speech development.At this visit, he was noted to have retrognathia, externally rotated ears, and a smooth philtrum.He had consistently poor follow-up due to social factors.Patient was in foster care and then adopted, so family history is limited (Figure 1).
At his 8-month checkup, he was noted to have delayed communication, gross motor, fne motor, problem-solving, and personal-social skills.He was found to have consistent deep airway penetration and airway aspiration with a negative cough response on barium swallow and a concern for hearing impairment.Referrals were placed to audiology, speech therapy, physical therapy, and occupational therapy at this time.Chest x-ray obtained for aspiration concerns revealed possible right atrial and ventricular enlargement and cardiology consulted.Echocardiogram showed no congenital abnormalities.
He presented to the emergency department at 15 months old with a febrile seizure that resolved, and he was discharged the same day.At 22 months, he was evaluated and showed a medium risk of autism based on the modifed checklist for autism in toddlers.He was admitted to the hospital at 2 years of age with multiple generalized tonicclonic seizures, and a head CT showed prominent lateral and third ventricles.Neurology was consulted, and he was started on levetiracetam.During his follow-up with neurology, his mom reported a history of staring spells daily lasting up to a few minutes where he would not interact with her if she tried to get his attention.Levetiracetam was increased and trileptal started.A brain MRI at age 2.5 years showed nodular gray matter heterotopia in the posterior right temporal lobe adjacent to the trigone of the right lateral ventricle and in the left posterior frontal lobe gray-white matter junction.Te cerebral ventricles were also mildly prominent in size.A swallow study at 3 years old showed fash airway penetration with thin liquids and had subsequent G tube placement.He has received all ageappropriate vaccinations.
He was seen by genetics for the frst time at 3.5 years.At this initial visit, his weight was 1 percentile, height was 10 percentile, body mass index (BMI) was 1 percentile, and head circumference was <3 percentile with global developmental delay.Te patient is unable to speak at this point.He ambulates independently but has frequent falls.On exam, he had microcephaly with a broad and tall forehead, low set, posteriorly rotated ears with a thin upper lip, and pointed chin (Figure 2).Te patient presented with foot abnormalities (Figure 3).Renal ultrasound normal and spine x-ray showed approximately 15 degree levoscoliosis of the lumbar spine with its apex at L3 (Figure 4).

Methods
A peripheral blood sample was collected and sent to GeneDx for analysis.Clinical information detailing characteristics such as developmental delay, cortical nodular heterotopia, autism spectrum disorder, microcephaly, and seizures were included to direct testing.GeneDx performed genomic DNA extraction directly from the specimen, focusing on the complete coding regions and splice site junctions across most of the human genome.Te analysis utilized NCBI RefSeq transcripts, and the human genome built GRCh37/ UCSC hg19.Sequence variants were reported following guidelines set by the Human Genome Variation Society (HGVS), while copy number variants were reported based on probe coordinates, exon coordinates, or specifc breakpoints when available.It was not stated if Sanger sequencing was utilized.No software such as Face2Gene was utilized.
Te peripheral blood sample was also sent for whole genome CMA, Fragile X, and mitochondrial genome through GeneDx.At this point, diferential diagnosis was

Discussion
We presented a case of a 3.5-year-old male with MRD7 caused by a previously unknown mutation in DYRK1A.
DYRK1A is a highly conserved tyrosine kinase that plays a role in signaling, mRNA splicing, chromatin transcription, DNA damage repair, cell survival, cell cycle control, neuronal development and functions, and synaptic plasticity.Activation of DYRK1A relies on intrinsic phosphorylation of a conserved tyrosine residue.Dephosphorylation does not inactivate DYRK1A once it has been activated, demonstrating its necessity for activation but not for maintenance.Haploinsufciency results in dysfunction that widely afects the patient, given that DYRK1A normal function is required in a multitude of processes.
Intellectual developmental disorder, autosomal dominant 7 (MRD7) or DYRK1A-related intellectual disability syndrome (OMIM 614014), results in an autism spectrumlike disorder with distinct physical characteristics.Tese include sparse scalp hair, bitemporal narrowing, deeply set eyes, periorbital fullness, short nose with high nasal root and pointed nasal tip, prominent ears with underdeveloped ear lobes, variations of the philtrum, thin vermillion border of the upper lip, short chin with horizontal crease and/or chin dimple, microcephaly, and foot abnormalities.Patients frequently require a multitude of treatments and therapies including speech, occupational therapy, physical therapy, and management of frequently occurring medical conditions including epilepsy [2].Tis is due to the role DYRK1A plays in many processes.

Figure 1 :
Figure 1: Pedigree limited as the patient is adopted.